We have recently uncovered a novel, intramolecular, tandem benzyne-forming/trapping process in which a 1,3-diyne cycloadds to a monoyne to produce an annulated benzenoid. We call the benzyne-forming stage a hexa-dehydro Diels-Alder (HDDA) reaction and the overall process an HDDA cascade. We show many exciting and highly efficient examples that serve to demonstrate the considerable versatility and power of this transformation. This thermal reaction proceeds in a catalyst- and reagent-free manner and is highly convergent and atom economical. It allows access to highly complex benzyne intermediates that would be difficult, if not impossible, to prepare by any conventional benzyne synthesis. This discovery will lead to a major impact through a fundamentally new body of research-a rare opportunity in contemporary synthetic chemistry. A very large portion (>70%) of top-selling drugs contain a benzenoid ring. In nearly half of these, the arene is fused to one or more additional rings (often heterocyclic in nature), comprising a polycyclic unit. Only a few strategies for de novo synthesis of benzenoids exist, and none is highly general. The HDDA cascade strategy is amenable to the synthesis of a wide array of pharmaceutically relevant, benzo-fused heterocycles. We have organized the project under two Aims, which parallel the benzyne-forming (Stage I) and -trapping (Stage II) events. SubAims a) and b) in each further segregate the studies into the categories of intra- vs. inter- molecular reactions, respectively. This research will lead to two categories of significant outcomes: (1) Enabling technology for synthesis of drug-like molecules, encompassing new paradigms valuable in both drug discovery and drug manufacturing (process) activities, will have emerged; (2) New fundamental insights and understanding of benzyne reactivity and altogether new reaction classes will have emerged. The HDDA-cascade process represents virtually unexplored territory. This research will allow chemists to think about, plan, and perform arene synthesis in new ways.